Recurrent CMV Viremia Portends Poor Prognosis and Results in Significant Resource Utilization in Patients with Poor Graft Function Post Allogeneic Stem Cell Transplantation

Introduction Poor Graft Function (PGF) characterized by 2 or more lineage cytopenias in the setting of complete donor chimerism is a recognized complication of allogeneic stem cell transplantation (alloSCT). Recurrent CMV viremia jeopardizes blood count recovery in PGF through direct effect of the virus on bone marrow function as well as myelosuppression/organ toxicity due to widely available antivirals such as val/ganciclovir or foscarnet. Methods To assess the clinical effect and resource utilization of recurrent CMV viremia on patients with PGF we performed a retrospective analysis of alloSCT recipients at our Centre from 2018-2019. Patients were classified as having PGF based on the following parameters: 1) Donor myeloid chimerism ≥95% at last assessment, 2) 2 or more lineage cytopenias defined by Hb ≤85g/L, Neutrophils ≤1.0x10 9/L, Platelets ≤60x10 9/L, 3) cytopenias present for 10 days after D30. CMV viral loads were monitored by q PCR twice weekly with reactivation defined as the first reading quantifiable above the threshold of detection of the assay. Recurrent CMV reactivation was defined as detectable CMV after an interval of 4weeks without detectable virus, with patients who reactivated within 4 weeks of an undetectable viral load defined as prolonged persisting infection. Patients who died before D60 or who relapsed within the 1 st 100 days or those who had a prior alloSCT were excluded. Baseline factors in the CMV seropositive PGF group were evaluated by Chi Squared and Kruskall-Wallis test for categorical and continuous variables respectively to establish any associations with recurrent or persisting CMV. Survival analysis of PGF patients was performed by the Kaplan Meier method with patients stratified by the following: Recurrent CMV/Prolonged persisting infection (RP-CMV), Single CMV reactivation (S-CMV), No CMV reactivations (N-CMV) and CMV sero-negativity (S-NCMV). A descriptive analysis of the number of hospital admissions in addition to the initial alloSCT admission (extra admissions) and total hospital days was also performed. Results There were 155 eligible patients of which 38 (24%) fulfilled criteria for PGF. The median follow-up of the cohort was 26 months (95%CI:23.1-28). The median overall survival (OS) of the cohort was not reached with an estimated 2 year OS of 73%. The 2 year OS of PGF patients was 59% compared to 78% in the non PGF group. There were no significant baseline associations found with RP-CMV (Table 1). Figure 1 demonstrates the survival of patients by nature of CMV reactivation. The 2 year OS by CMV reactivation was as follows: RP-CMV 25%, S-CMV 68%, N-CMV 70%, SN-CMV 87%. On univariate analysis, RP-CMV was significantly associated with mortality [HR 5.41; 95%CI 1.80-16.28; P=0.003]. This association remained significant when including Age and grade III-IV GVHD in multivariate analysis: RPCMV [HR 7.57; 95%CI 2.20-25.9;P=0.0013=], Age [HR 1.03; 95% CI 0.99-1.08; P=0.16] and GVHD [HR 2.91; 95%CI 0.87-9.75; P=0.08]. RP-CMV was not a risk factor for mortality within the NPGF population [HR 0.75; 95%CI 0.29-01.97; P=0.56]. Those with RP-CMV experienced an increase in their CMV viral load within a median of 4 days range (2-86) after achievement of an undetectable result. Those with PGF and RP-CMV had an average of 1.4 extra admissions with an average length of stay of 80 days, those with S-CMV reactivation had an average of 1.6 extra admissions with an average length of stay of 35 days, and those with N-CMV had an average of 1 extra admission with an average length of stay of 17 days. Those with SN-CMV had an average of 1 extra admission with an average length of stay of 23 days. CMV reactivation and CMV therapy contributed to 13/17 (76%) total readmissions for those with RP-CMV compared to 5/13 (38%) readmissions for those with S-CMV. Conclusion Patients with PGF and RP-CMV are at high risk of mortality as well as more lengthy hospital admissions of which CMV reactivation and CMV therapy is a potential contributor. Targeted use of novel therapies to prevent CMV reactivation in patients with PGF may improve both bone marrow function and survival leading to less resource utilization. Figure 1 Figure 1. Disclosures Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Koldej: CRISPR Therapeutics: Research Funding. Ritchie: BMS: Research Funding; Takeda: Research Funding; CRISPR Therapeutics: Research Funding; Amgen Inc: Honoraria, Research Funding; CSL: Honoraria; Novartis: Honoraria.

Use of Cryopreserved Allogeneic PBSC Results in Delayed Engraftment and Increased Incidence of Poor Graft Function

Use of Cryopreserved Allogeneic PBSC Results in Delayed Engraftment And Increased Incidence of Poor Graft Function Introduction: During COVID Pandemic, national and international transplant centres agreed to use cryopreserve the donor PBSC as a safer option to deliver allogeneic transplants. Published data suggests that use of cryopreserved allogeneic PBSC is safe and comparable to use of fresh PBSC but cryopreservation of stem cells may lead to cell loss and hence efficacy. During COVID pandemic, use of cryopreserved allogeneic PBSC was adopted as policy on 01/06/2020. This look back analysis evaluates the impact of change in policy. Aims: Evaluate Engraftment time, compare with historical data, blood component support, and use of growth factors Methods and Materials: Data was collected from health records (paper and electronic) and laboratory records. Transplant features and engraftment kinetics were analysed. Results: Group A June 2020 to November 2020, 19 patients [M: 13; F: 6; median age: 50yr (range: 23-69)] who received cryopreserved allogeneic PBSC were compared to 35 patients [M:24; F:11; median age: 59yr (range: 21-71)] receiving fresh allogeneic PBSC for engraftment kinetics. There were no differences between two groups regarding underlying diagnosis (p=0.31), sex mismatch, CMV mismatch, blood group mismatch, reduced intensity conditioning [RIC](p=0.28), type of donor (p=0.98) or use of Alemtuzumab (p=0.88). Median infused Cell dose in group A was 5.3 (3.4-7.16) and in group B 4.9 (1.03-6.85), [p=0.11]. Neutrophil engraftment was significantly faster with fresh PBSC as compared to cryopreserved PBSC (16d vs. 25d, p=0.0025) predominantly with MUD (18d vs. 27d, p=0.009) and RIC (16d vs. 25d, p=0.009). Platelet engraftment to 25 was faster with fresh PBSC (13d vs. 20d, p=0.021) with delayed engraftment in MUD (20d vs. 13d, p=0.006) and RIC (23d vs. 13d, p=0.039). Day to engraftment per unit CD34 was shorter with fresh PBSC for neutrophils (median: 3.2, range: 2.0-7.7 vs. 5.3, range: 2.5-16.7; p=0.006) and platelets (median: 2.4, range: 1.7-25 vs. 3.8, range: 2.2-25; p=0.001) but only for MUD. This suggests 35-40% less efficiency with use of cryopreserved PBSC. There was no difference in the need for transfusion support [RBCs (6 units vs. 3 units, p=0.32); platelets (5 pools vs. 7 pools, p=0.33)]. G-CSF use was higher with cryopreserved PBSC in RIC (54% vs. 20%, p=0.031). Two patients experienced TRM before day 90 (3.7%). At day 90, 17/52 (32.7%) had cytopenia in one lineage and 8/52 (16%) had cytopenia in more than one lineage. Delayed engraftment was observed in 10 of 33 patients (30.3%) transplanted in 2020 and the only significant association was use of cryopreserved PBSC (0% vs. 53%, p=0.001). There was no difference in the incidence of aGVHD, hepatic VOD, microangiopathy and bacterial infections. Numbers are not sufficient to make disease specific comparisons. Conclusion: Cryopreserved PBSC result in delayed neutrophil and platelet engraftment predominantly with MUDS and RIC. Incidence of delayed engraftment and poor graft function is higher. Per unit CD34 dose, cryopreserved PBSC are 30-40% less efficient to achieve engraftment. Delayed engraftment with cryopreserved PBSC especially in MUD raises the possibility that time from harvest to cryopreservation contributes to reduced efficacy. Based on these findings it was decided to infuse higher CD34 dose (6-7x10^6/kg as compared to usual 4-5x10^6/kg) for cryopreserved MUD PBSC. Disclosures Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria.

Clinical features, pathophysiology and therapy of Poor Graft Function Post Allogeneic Stem Cell Transplantation

Poor graft function (PGF) defined by the presence of multi-lineage cytopenias in the presence of 100% donor chimerism, is a serious complication of allogeneic stem cell transplant (alloSCT). Inducers or potentiators of allo-immunity such as CMV reactivation and graft versus host disease (GVHD) are associated with the development of PGF, however more clinical studies are required to establish further risk factors and describe outcomes of PGF. The pathophysiology of PGF can be conceptualized as dysfunction related to the number or productivity of the stem cell compartment, defects in bone marrow microenvironment components such as mesenchymal stromal cells and endothelial cells, or immunological suppression of post alloSCT haematopoiesis. Treatment strategies focused on improving stem cell number and function and microenvironment support of haematopoiesis have been attempted with variable success. There has been limited use of immune manipulation as a therapeutic strategy, but emerging therapies hold promise. This review details the current understanding of the causes of PGF and methods of treatment to provide a framework for clinicians managing this complex problem.

Outcomes with CD34 stem cell boost for poor graft function after allogeneic hematopoietic stem cell transplantation for hematologic malignancies: A systemic review and meta-analysis.

e19021 Background: Poor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HCT) characterized by severe multilineage cytopenia in the absence of mixed donor chimerism, relapse, or severe graft-vs-host disease (GVHD). We present a systemic review and meta-analysis aimed to assess the outcomes with stem cell boost (SCB) for PGF in adult allo-HCT patients. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, 752 articles were screened from 4 databases (PubMed, Embase, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for “hematological malignancies”, “hematopoietic stem cell transplantation”, “CD34 antigen(s)” and “treatment outcome(s)” from the date of inception to Jan 2021. After excluding review, duplicate and non-relevant articles, we included 8 studies (1 prospective, 7 retrospective) reporting hematologic complete/overall response rate (CR/ORR), GVHD and overall survival (OS) after SCB for PGF after Allo-HSCT. Quality evaluation was done using the NIH quality assessment tool. Pooled analysis was done using the ‘meta’ package (Schwarzer et al, R programming language) and proportions with 95% confidence intervals (CI) were computed. Inter-study variance was calculated using Der Simonian-Laird Estimator. Results: We identified 217 patients who received SCB for PGF after allo-HCT. Median age, time since transplant and SCB dose were 48 (37-54) years, 133 (113-450) days and 3.43 (1.7-4.9) million CD34 cells/kg respectively. CR and ORR were 71% (95%CI 0.63-0.77, I216%) and 80% (95%CI 0.74-0.85, I20%) respectively. After median follow up of 41.5 (5-77) months, actuarial survival rate (ASR) was 54% (95%CI 0.48-0.61, I20%). OS was reported from 80% (1y) to 40% (9y) Acute and chronic GVHD incidence after SCB was 17% (95% CI 0.12-0.23, I2=0%) and 17% (95% CI 0.08-0.32, I2=72%, n=197) respectively, and 25% (95% CI 0.14-0.39, I2=63%, n=163) deaths were due to relapse (Table). Conclusions: CD34 SCB improves outcomes after PGF after allo-HSCT with acceptable toxicity profile. However, current literature lacks high-quality randomized evidence and there remains an unmet need for prospective studies to address optimal dosing and manipulation of SCB. Outcomes with SCB for PGF after allo-HCT (n=217).[Table: see text]